The peripheral vasculature must control blood flow and effect the exchange of substances between tissues and blood. These two processes are regulated by vascular smooth muscle cells whose contractile activity is determined by both extrinsic mechanisms such as nerves and intrinsic mechanisms arising by virtue of interactions between tissue demands and vascular behavior. The control of blood flow and capillary exchange by intrinsic mechanisms is called local regulation and is the subject of the research proposed in this grant. A precise quantitative description of the mechanisms involved in local blood flow regulation requires two types of information which are exceedingly difficult to obtain from intact tissues. These are the regional sensitivity of vascular smooth muscle to vasoactive agents and the concentrations of vasoactive substances in the tissues during regulation of blood flow and exchange. We propose to carry out a research program which will make use of direct measurements at the microcirculatory level, on isolated vascular smooth muscle, and on perfused tissues to obtain these data. Using recently developed micro techniques, concentration measurements will be made at the site of action of substances pertinent to local regulation of flow. In addition, selective application of these substances to single microvessels will be accomplished using microiontophoresis and microsuffusion. The specific questions to be approached are: 1. What is the reactivity of vascular smooth muscle to certain stimuli relevant to local regulation of blood flow, particularly oxygen, potassium and osmolality? 2. What are the concentrations of these substances normally, and how do they change during regulation of blood flow? 3. How does in vitro vascular smooth muscle reactivity compare with in vivo reactivity? 4. What are the differences in behavior of the various series elements of the microcirculation?